Differentiation is a process whereby structures and functions of cells are progressively committed to give rise to more specialised cells, such as the formation of T cells or B cells from immature haematopoietic precursors. Therefore, as the cells become more committed, they become more specialised. In the majority of mammalian cell types, cell differentiation is a one-way process leading ultimately to terminally differentiated cells. However, although some cell types persist throughout life without dividing and without being replaced, many cell types do continue to divide during the lifetime of the organism and undergo renewal. This may be by simple division (e.g. liver cells) or, as in the case of cells such as haematopoietic cells and epidermal cells, by division of relatively undifferentiated stem cells followed by commitment of one of the daughter cells to a programme of subsequent irreversible differentiation. All of these processes, however, have one feature in common: cells either maintain their state of differentiation or become more differentiated. They do not become undifferentiated or even less differentiated.
Retrodifferentiation is a process whereby structures and functions of cells are progressively changed to give rise to less specialised cells. Some cells naturally undergo limited reverse differentiation (retrodifferentiation) in vivo in response to tissue damage. For example, liver cells have been observed to revert to an enzyme expression pattern similar to the foetal enzymic pattern during liver regeneration (Curtin and Snell, 1983, Br. J. Cancer. Vol. 48; 495-505).
In WO96/23870 it was shown that it was possible to treat differentiated cells so that they became undifferentiated cells, including stem cells. These undifferentiated cells were capable of proliferating and giving rise to redifferentiated progeny of the same lineage or any other lineage. In the case of retrodifferentiated haematopoietic cells, these stem cells are pluripotent and can give rise to more than one cell lineage. The seminal finding of WO96/23870 were completely unexpected.
The clinical implications of this finding are enormous. Stem cells are extremely difficult to obtain from human patients. They are typically obtained from umbilical tissue, bone marrow or blood where they are present in only very small amounts. However, the present invention provides a device for producing stem cells from more committed cells, in particular by the process of retrodifferentiation.
U.S. Pat. No. 6,087,168 discloses a method of transdifferentiating epidermal cells into neuronal cells, in which method epidermal cells are dedifferentiated or retrodifferentiated with an appropriate medium. Likewise, Lake J A et al Journal of Cell Science 113, 556-566 (2000) and Rathjen J et al Journal of Cell Science 112, 601-612 (1999) disclose the retrodifferentiation of embryonic stem (ES) cells into early primitive ectoderm-like (EPL) cells, in response to two separable factors.